For the past several years, we have studied new methods for the synthesis of beta-keto phosphonates, compounds with a pattern of functionality that results in extraordinary versatility as synthetic intermediates. The methods we have discovered are based on use of phosphorus electrophiles for formation of the C-P bond, and are inherently complementary to classical methods which rely upon nucleophilic phosphorus reagents. Through further development of this new methodology, it should be possible to obtain beta- keto phosphonate derivatives of common nucleosides. Specifically we propose to: 1) develop a reliable route to 3'-phosphono- 2'-ketonucleosides, compounds which could be classed as beta-keto phosphonates, and then convert these compounds to their 2'-hydroxy and 2'- deoxy analogues; 2) investigate known reactions of beta-keto phosphonates with our initial targets, reactions such as the Wadsworth-Horner-Emmons condensation and the Horner elimination; and, 3) develop a new synthesis of 3'-methylenephosphononucleosides, compounds which are true isosteres of nucleoside 3'-phosphates. While some of our target compounds may have direct anti-viral activity, their primary value lies in their potential as synthetic intermediates. Since the finding that 3'-azido-3'-deoxythymidine (AZT) is therapeutically useful in the treatment of AIDS, there has been tremendous surge of interest in the preparation of modified nucleosides. Furthermore, the growing interest in oligonucleotide mimics demands more facile access to stable analogues of natural nucleotides. By developing the chemistry described in this proposal, we would establish methodology for the synthesis of an almost endless variety of 2'-and/or 3'-modified nucleosides, and foster efforts to separate the anti-viral activity of nucleosides analogues from their cytotoxicity.